Project Summary/Abstract Cancer cachexia severely depletes skeletal muscle mass leading to impairments in physical function and a diminished quality of life. In the clinical realm, malnutrition and cachexia are synonymous. However, cachexia is more complex than mere caloric deficiency, since improving nutritional status does not reverse or prevent muscle wasting. Our preliminary data show that the response of skeletal muscle protein to the anabolic stimulus of amino acids is impaired in cancer patients. We propose that the dysregulation of skeletal muscle protein balance in cancer patients is altered by persistent systemic and localized skeletal muscle inflammation derived from tumoral and humoral catabolic factors. Specifically, these factors alter the regulation of muscle protein balance by affecting both synthesis and breakdown. Synthesis is affected because catabolic factors diminish the plasma concentrations of key branched-chain amino acids such as leucine, thereby suppressing the stimulus for nutrition-derived anabolism. Breakdown is affected because catabolic factors such as tumor necrosis factor-? (TNF-?) enhance nuclear factor-?B (NF-?B), which in turn activates muscle proteolysis via the ubiquitin-proteasome system. Our data demonstrate that skeletal muscle in cancer patients exhibits increased activation of NF-?B and enhanced inflammatory burden. More recently, we found that 3 months of testosterone therapy downregulates ubiquitin and the E3 ubiquitin ligases MuRF1 and MAFbx/Atrogin-1 gene expression along with blocking cleavage of a novel 14-kD actin fragment in the initial step of actomyosin destruction. Our general hypothesis is that the antianorectic and anticachectic effects of leucine-enhanced essential amino acids (L-EAA) supplemented concomitantly with testosterone's anabolic and anticatabolic properties will enhance lean muscle mass in patients with advanced (stages IIB, IIIA and IIIB) or recurrent cervical carcinoma by increasing the stimulus for protein synthesis, and by inhibiting the activation of muscle proteolysis, respectively. We will conduct a randomized, double-blind, placebo-controlled intervention study designed to clinically and mechanistically assess novel nutritional (L-EAA) and pharmacologic (testosterone) therapies aimed at preventing or normalizing cancer-related muscle wasting in conjunction with standard of care (SOC) treatment. We will determine the efficacy of this novel therapeutic approach on the following outcome measures in patients with advanced or recurrent cervical carcinoma: 1) lean body mass and muscle strength, 2) muscle protein turnover, and 3) inflammatory biomarkers and signaling pathways of atrophy in skeletal muscle.